Influenza virus is a global health threat that is responsible for over 300,000 deaths annually. The virus evades immune recognition by engaging in a combination of accelerated antigenic drift, domain reassortment, genetic recombination, and glycosylation based masking of its surface glycoproteins. This rapid mutation capability of the virus is particularly exacerbated in the context of the growing threat from the present H1N1 ‘swine flu’ pandemic as well as the alarming worldwide spate in recent infections with highly pathogenic avian H5N1 ‘bird flu’ influenza strains. (Khanna et al., Journal of Biosciences, 33(4):475, 2008, Soundararajan et al., Nature Biotechnology 27:510, 2009). Furthermore, two of the major flu pandemics of the last century originated from avian flu viruses that changed their genetic makeup to allow for human infection.
Given the high degree of unpredictability in evolution of these influenza viruses, there is a need for the development of cross-strain effective (universal or broad spectrum) anti-influenza prophylactics and therapeutics. Such universal or broad spectrum anti-influenza agents would augment the annual flu vaccines that are designed to target specific ‘seasonal’ viral strains in circulation. (Ekiert et al., Science, 324(5924):246, 2009 and Sui et al., Nat Struct Mol Biol. 16(3):265, 2009). The importance of such agents is highlighted by the emerging drug resistance to antivirals oseltamivir (TAMIFLU®)/zanamivir(RELENZA®) (NA-inhibitors) and Amantadine/Rimantadine (MP-2 inhibitors) (Collins et al., Nature 453:1258, Stouffer et al., Nature, 451:596, 2008, Pielak et al., Proc. Natl. Acad. Sci. USA, 106:7379, 2009). For instance, over 98% and 100% of H1N1 strains this season are resistant to oseltamivir (TAMIFLU®) and the adamantane derivatives (Amantadine/Rimantadine), respectively. Additionally, seasonal flu vaccines are developed based on predictions of the most virulent influenza strain. In some cases, these predictions are wrong, thereby making the seasonal flu vaccines less effective. For these reasons, there is a need for the development of broad spectrum vaccines and therapeutic agents that are effective in the treatment or the delay of onset of disease caused by influenza viruses, independent of subtype or clade. Of course, there is also significant value in agents that are effective against any influenza strain, and indeed there can be profound value in agents that are specific to one or a set of strains.